Diabetes and the Brain (Contemporary Diabetes)

Diabetes and the Brain

Contemporary Diabetes A RISTIDIS V EVES , MD, DS C SERIES EDITOR

The Diabetic Foot: Second Edition, edited by Aristidis Veves, MD, John M. Giurini, DPM, and Frank W. LoGerfo, MD, 2006 The Diabetic Kidney, edited by Pedro Cortes, MD and Carl Erik Mogensen, MD, 2006 Obesity and Diabetes, edited by Christos S. Mantzoros, MD, 2006 Diabetic Retinopathy, edited by Elia J. Duh, MD, 2008 Diabetes and Exercise: edited by Judith G. Regensteiner, PhD, Jane E.B. Reusch, MD, Kerry J. Stewart, EDD, Aristidis Veves, MD, DSc, 2009 Diabetes and the Brain, edited by Geert Jan Biessels, MD, PhD, Jose A. Luchsinger, MD, MPH

D IABETES AND THE B RAIN

Edited by

Geert Jan Biessels, MD, PhD University Medical Center, Utrecht, The Netherlands

Jose A. Luchsinger, MD, MPH Columbia University College of Physicians and Surgeons, New York, NY, USA

Editors Geert Jan Biessels Department of Neurology Rudolf Magnus Institute of Neuroscience University Medical Center Utrecht PO Box 85500 Utrecht 3508 GA Utrecht The Netherlands [email protected]

Jose A. Luchsinger Columbia University Medical Center Presbyterian Hospital 622 West 168th St. New York, NY 10032 USA [email protected]

ISBN 978-1-60327-849-2 e-ISBN 978-1-60327-850-8 DOI 10.1007/978-1-60327-850-8 Library of Congress Control Number: 2009933948 © Humana Press, a part of Springer Science+Business Media, LLC 2009 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper springer.com

Preface

Diabetes, particularly type 2 or adult onset diabetes, is increasing in prevalence in the world. In the United States the prevalence of diabetes is over 12% in persons of age 60 years and older. The prevalence in Europe is 8–10% and catching up with the United States. The trend worldwide is for this prevalence to increase given the epidemic of overweight and obesity (2/3 of the adult United States population is overweight or obese). Thus, the fact that diabetes affects the brain is of enormous public health importance. While acute cerebral complications of diabetes, such as hypoglycemia or stroke, are well recognized, more chronic cerebral conditions, such as cognitive and mood disorders, have failed to be recognized until recently. The last few decades have yielded new insights linking type 2 diabetes to dementia and other cognitive disorders and into the cognitive consequences of type 1 diabetes. Hence, the impact of diabetes on the brain has become a very multifaceted topic. Clinical care and research on cerebral complications of diabetes now involve internists, neurologists, psychiatrists, psychologists, and basic scientists. There has been a surge in pre-clinical and clinical research papers ranging from topics such as management of hyperglycemia in acute stroke to disturbances in insulin signaling in Alzheimer’s disease. This has led to substantial progress in the field, but it also makes it more difficult for those involved to keep track of all relevant developments. This book provides an update on the acute and chronic consequences of diabetes in the brain. We brought together experts from around the world in order to provide a helicopter view of this intriguing topic. The book offers not only in-depth reviews on cerebral complications of diabetes, but also introductory chapters on current insights into the pathophysiology and clinical management of diabetes and its complications and on stroke, neuropsychological assessment and dementia. With these “update on diabetes for neurologists” and “update on stroke and dementia for diabetologists” we hope to offer relevant and easily accessible background information that puts the cerebral complications of diabetes into context. The target audience of this book is broad and includes medical specialists taking care of persons with diabetes and researchers in the diabetes field. It is important to point out that most clinicians and researchers think that the only complications of diabetes are microvascular (retinopathy, renal, neuropathy) and macrovascular (heart disease and stroke). Given increased longevity, the v

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Preface

aging of our societies, and the increasing prevalence of diabetes, the chronic consequences of diabetes in the brain are at least as important but have failed to acquire the recognition that more traditional complications have. We believe that this book will bring the consequence of diabetes in the brain to the mainstream and thus has the potential to change the field. We thank Aristidis Veves, from Harvard Medical School, Boston, for inviting us to put together this book for the Humana Press “Contemporary Diabetes” series, for which he is the series editor. We would also like to thank Paul Dolgert and Connie Walsh from Springer Science and Business Media for their help and support. Finally, we thank the authors, all internationally distinguished in their fields, for their invaluable contributions to this book. Geert Jan Biessels José A. Luchsinger

Contents

PART I

U PDATE

ON

D IABETES

FOR

N EUROLOGISTS

1 Type 1 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . Edith W.M.T. ter Braak and Aline M.E. Stades

3

2 Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . Hermes J. Florez, Alex A. Sanchez, and Jennifer B. Marks

33

PART II U PDATE

ON

S TROKE

AND

D EMENTIA

FOR

D IABETOLOGISTS

3 Acute Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . L. Jaap Kappelle and H. Bart van der Worp

57

4 Neuropsychological Assessment . . . . . . . . . . . . . . . . . Roy P.C. Kessels and Augustina M.A. Brands

77

5 Clinical Evaluation and Treatment of Cognitive Dysfunction and Dementia . . . . . . . . . . . . . . . . . . . . 103 Laura A. van de Pol, Wiesje M. van der Flier, and Philip Scheltens PART III ACUTE C EREBRAL D ISTURBANCES

IN

D IABETES

6 Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Brian M. Frier 7 Ketoacidosis and Hyperglycemic Hyperosmolar State . . . . . . 159 Matthew Freeby and Susana Ebner 8 Stroke and Diabetes Mellitus . . . . . . . . . . . . . . . . . . . 183 Boris N. Mankovsky 9 Hyperglycemia in Acute Stroke . . . . . . . . . . . . . . . . . . 219 Nyika D. Kruyt and Yvo W.B.M. Roos PART IV L ONG -T ERM C EREBRAL C OMPLICATIONS

IN

D IABETES

10 Cognition in Children and Adolescents with Type 1 Diabetes . . 251 Christopher M. Ryan

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Contents

11 Cognition in Adults with Type 1 Diabetes . . . . . . . . . . . . . 277 Augustina M.A. Brands, Roy P.C. Kessels, and Christopher M. Ryan 12 Cognition in Type 2 Diabetes or Pre-diabetic Stages . . . . . . . 295 Esther van den Berg, Yael D. Reijmer, and Geert Jan Biessels 13 Type 2 Diabetes, Related Conditions, and Dementia . . . . . . . 323 José Alejandro Luchsinger 14 Diabetes and Depression . . . . . . . . . . . . . . . . . . . . . . 343 Maria D. Llorente and Julie E. Malphurs 15 Central Nervous System Involvement in Diabetic Neuropathy . . 365 Dinesh Selvarajah, Iain D.Wilkinson, Rajiv A. Gandhi, and Solomon Tesfaye PART V E XPERIMENTAL M ODELS

AND

PATHOPHYSIOLOGY

16 Animal Models . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 Geert Jan Biessels 17 Pathobiology of Diabetic Encephalopathy in Animal Models . . . 409 Anders A.F. Sima 18 The Role of Insulin Resistance in Age-Related Cognitive Decline and Dementia . . . . . . . . . . . . . . . . . 433 G. Stennis Watson and Suzanne Craft Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459

Contributors

GEERT JAN BIESSELS • Department of Neurology, G03.228, Rudolf Magnus Institute of Neuroscience, University Medical Center, 3508 GA Utrecht, The Netherlands, [email protected] AUGUSTINA M.A. BRANDS, PhD • Regional Psychiatric Centre/Zuwe Hofpoort Hospital, Woerden, The Netherlands; Helmholtz Institute, Utrecht University, Utrecht, The Netherlands, [email protected] SUZANNE CRAFT, PhD • Veterans Affairs Puget Sound, University of Washington, Geriatric Research, Education, and Clinical Center, Seattle, WA 98108, USA, [email protected] SUSANA EBNER, MD • Medicine Department, Columbia University, New York, NY, USA, [email protected] HERMES JOSE FLOREZ, MD, MPH, PhD • Associate Professor of Clinical Medicine and Epidemiology, Clinical Director Geriatric Research, Education and Clinical Center (GRECC), University of Miami Miller School of Medicine, Miami Veterans Affairs Healthcare System, Medicine Department, Divisions of Endocrinology and Geriatric Medicine, Miami, FL, USA, [email protected] MATTHEW FREEBY, MD • Department of Medicine, Columbia University, New York, NY, USA, [email protected] BRIAN M. FRIER, BSc (Hons), MD, FRCP (Edin), FRCP (Glas) • Diabetes Department, Edinburgh, Scotland EH16 4SA, UK, [email protected] RAJIV A. GANDHI, MBChB, MRCP • Sheffield Teaching Hospitals, NHS Trust, Diabetes, Sheffield S10 2JF, UK, [email protected] L. JAAP KAPPELLE • Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands, [email protected] ROY P.C. KESSELS • Radboud University Nijmegen, Donders Centre for Cognition, 6500 HE Nijmegen, The Netherlands; Helmholtz Institute, Utrecht University, The Netherlands; Donders Institute for Brain, ix

x

Contributors

Cognition and Behaviour, Radboud University Nijmegen and Radboud University Nijmegen Medical Centre, Nijmesen, The Netherlands, [email protected], [email protected] NYIKA D. KRUYT, MD • Department of Neurology, University of Amsterdam, 1100 DE Amsterdam, The Netherlands, [email protected] MARIA D. LLORENTE, MD • Chief, Psychiatry Service, Miami VA Healthcare System, Miller School of Medicine, University of Miami, Miami, FL, USA, [email protected] JOSÉ ALEJANDRO LUCHSINGER, MD, MPH • Florence Irving Associate Professor of Medicine and Epidemiology, Gertrude H. Sergievsky Center, Columbia Univeristy Medical Center, New York, NY, USA, [email protected] JULIE E. MALPHURS, PhD • Health Science Specialist, Miami VA Healthcare System, Assistant Professor of Psychiatry, Miller School of Medicine, University of Miami, Miami, FL, USA, [email protected] BORIS N. MANKOVSKY, MD • Institute of Endocrinology, Kiev Ukraine, [email protected] JENNIFER B. MARKS, MD • University of Miami Miller School of Medicine, Miami Veterans’ Affairs Medical Center, Miami, FL, USA, [email protected] YAEL D. REIJMER • Department of Neurology, G03.228, Rudolf Magnus Institute of Neuroscience, University Medical Center, 3508 GA Utrecht, The Netherlands, [email protected] YVO W.B.M. ROOS, MD, PhD • Department of Neurology, H2-218, Academic Medical Centre, University of Amsterdam, 1100 DE Amsterdam, The Netherlands, [email protected] CHRISTOPHER M. RYAN, PhD • Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, [email protected] ALEX AURELIO SANCHEZ, MD • Advanced Geriatrics Fellow, University of Miami Miller School of Medicine, Medicine Geriatrics, Miami, FL, USA, [email protected] PHILIP SCHELTENS, MD, PhD • VU University Medical Center, Alzheimer Center, Department of Neurology, Amsterdam 1007 MB, The Netherlands, [email protected]

Contributors

xi

DINESH SELVARAJAH, MBChB, MRCP • University of Sheffield, Diabetes Research, Royal Hallamshire Hospital, Sheffield S102JF, Yorkshire, UK, [email protected] ANDERS A.F. SIMA • Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA, [email protected] ALINE M.E. STADES, MD, PhD • Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands, [email protected] EDITH W.M.T. TER BRAAK, MD, PhD • Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands, [email protected] SOLOMON TESFAYE, MD, FRCP • Diabetes Department, Sheffield Teaching Hospitals, Sheffield S10 2JF, Yorkshire, UK, [email protected] ESTHER VAN DEN BERG • Department of Neurology, G03.228, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands, [email protected] WIESJE M. VAN DER FLIER, PhD • VU University Medical Center, Alzheimer Center, Department of Neurology, Department of Epidemiology and Biostatistics, Amsterdam 1007 MB, The Netherlands, [email protected] LAURA A. VAN DE POL, MD • VU Medical Centre, Department of Neurology, 1007 MB Amsterdam, The Netherlands, [email protected] H. BART VAN DER WORP, MD, PhD • Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands, [email protected] G. STENNIS WATSON, PhD • University of Washington, Psychiatry and Behavioral Sciences, Seattle, WA 98108, USA, [email protected] IAIN D. WILKINSON, MSc, PhD, FIPEM, ARCP • University of Sheffield, Academic Radiology, Royal Hallamshire Hospital, Sheffield S102JF, UK, [email protected]

1

Type 1 Diabetes Edith W.M.T. ter Braak and Aline M.E. Stades CONTENTS I NTRODUCTION E PIDEMIOLOGY PATHOPHYSIOLOGY S HORT-T ERM C OMPLICATIONS L ONG -T ERM C OMPLICATIONS T REATMENT L IFESTYLE L IVING W ITH D IABETES R EFERENCES

Abstract Type 1 diabetes is a life long metabolic disorder that is characterized by absolute insulin deficiency resulting in hyperglycemia and lipolysis. Type 1 diabetes accounts for 5–10% of the total diabetes population, the majority of the other patients has type 2 diabetes. Insulin deficiency originates with autoimmune mediated β-cell destruction. Without insulin treatment, type 1 diabetes leads to dehydration and ketoacidosis and can ultimately be fatal. Prolonged exposure to hyperglycemia is responsible for microvascular damage in the eye, kidneys and nervous system and contributes to macrovascular disease of the coronary, cerebral and peripheral arteries. Limited joint mobility and the diabetic foot are other complications related to chronic hyperglycemia. Currently, the corner stone of the treatment of type 1 diabetes is exogenous insulin substitution aiming to restore near-normal glycemia in order to prevent or delay long-term complications. Recurrent hypoglycemia is a frequent complication and a serious burden for both patients and their significant others. Additional therapeutic interventions consist of lifestyle modifications, particularly aiming From: Contemporary Diabetes: Diabetes and the Brain Edited by: G. J. Biessels, J. A. Luchsinger (eds.), DOI 10.1007/978-1-60327-850-8_1  C Humana Press, a part of Springer Science+Business Media, LLC 2009 3

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ter Braak and Stades

to reduce cardiovascular risk factors. In the future,the necessity for substitution with exogenous insulin may be replaced by β-cell transplantation or even preventive β-cell preservation. Patients must receive proper education and support, since they have to manage their chronic disease on a daily basis. Key words: Type 1 Diabetes; Insulin; Ketoacidosis; Hyperglycemia; Hypoglycemia; Autoimmune; β-cells; Long-term complications; Education; Self-care.

INTRODUCTION The current classification of diabetes in different subtypes is based on the defect(s) that causes hyperglycemia, namely, aberrant or deficient insulin secretion or insufficient insulin action (1). Type 1 diabetes (T1D) originates from autoimmune-mediated destruction of the pancreatic β-cells that normally produce insulin, thus resulting in absolute insulin deficiency. Other types of pancreatic disease involving destruction of the β-cells, such as alcoholic pancreatitis, are classified otherwise. Previously, T1D was also known as juvenile-onset diabetes or insulin-dependent diabetes mellitus (IDDM). However, these expressions may result in misclassification and indistinct prognosis and therapeutic options. Criteria to diagnose T1D are shown in Table 1 (1). Note that diagnostic criteria do not include HbA1c levels, which are exclusively used to follow glycemic control, but not diagnosis. Table 1 Diagnostic criteria for diabetes mellitus (ADA) Diabetes mellitus (overall) Symptoms of polyuria, polydipsia, unexplained weight loss or Random plasma glucose ≥ 11.1 mmol/l (200 mg/dl) on 2 subsequent days or Fasting (>8 h) plasma glucose ≥ 7.0 mmol/l (126 mg/dl) on 2 subsequent days Type 1 diabetes mellitus Autoantibody GAD positive and/or autoantibody tyrosine phosphatase IA-2/IA-2β or Presenting with ketoacidosis Additional criteria for diabetes mellitus type 1 (used for research purposes) Fasting C-peptide 20 intraretinal hemorrhages in 4 quadrants or definite venous beading in ≥2 quadrants or prominent intraretinal microvascular abnormalities in ≥1 quadrant NO signs of proliferative retinopathy ≥1 of: neovascularization, vitrous/preretinal hemorrhage

Severe nonproliferative

Proliferative

1 Adapted from Wilkinson et al. and the Global Diabetic Retinopathy Project Group (26).

Screening for diabetic retinopathy with dilated pupils by an ophthalmologist is recommended within 5 years after the onset of diabetes and annually thereafter. Screening is necessary because retinopathy remains asymptomatic until macular edema and/or proliferative diabetic retinopathy are present and by then it may be too late for effective treatment aiming at symptom relief and slowing progression. Macular edema results from capillary leakage and can develop at all stages of retinopathy. It typically presents with the gradual onset of blurring of near and distant vision in patients who have other evidence of microvascular eye disease, such as perimacular microaneurysms. Apart from glycemic control hypertension is also a risk factor for retinopathy. The efficacy of laser photocoagulation in preventing visual loss from proliferative diabetic retinopathy is well-established in randomized trials. Importantly, the presence of retinopathy should not be considered a contraindication to the prescription of salicylates which may be indicated for other reasons, because this treatment does not increase the risk of retinal hemorrhage. Apart from retinopathy, other eye diseases are related to diabetes. Cataract is much more frequent in patients with diabetes and tends to become clinically significant at a younger age. Glaucoma is markedly increased in diabetes too.

Type 1 Diabetes

13

Diabetic Neuropathy The ultimate consequences of diabetic neuropathy include such grave conditions as impaired mobility, limb amputation, and progressive deformities particularly of the feet. Diabetic neuropathies are heterogeneous with diverse clinical manifestations including symmetric polyneuropathy, autonomic neuropathy, radiculopathies, mononeuropathies, and mononeuropathy multiplex. However, not all peripheral neuropathy in diabetes patients is caused by diabetes (27, 28). Attention should be paid to other potential causes of neuropathy, such as monoclonal gammopathy, folic acid or vitamin B12 deficiency, extensive use of alcohol, and co-existing chronic inflammatory demyelinating polyneuropathy (CIDP). The need for annual screening for diabetic neuropathy in all patients is discussed in the subsection of foot care. Diabetic polyneuropathy is primarily a symmetrical sensory neuropathy that gradually causes the typical “stocking-glove” sensory loss at progression. Various staging systems for use in research and for clinical purposes exist. Diabetes is the most common cause of neuropathic (Charcot) arthropathy in the Western world. A warm, swollen foot in a diabetic patient with long-standing neuropathy without local or systemic signs of infection is consistent with Charcot’s disease and calls for abstinence from putting weight on the foot until symptoms subside. Major clinical manifestations of diabetic autonomic neuropathy include resting tachycardia, orthostatic hypotension, disturbances of gastrointestinal motility, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, and hypoglycemic autonomic failure resulting in impaired glucose counterregulation in case of hypoglycemia. Bladder dysfunction may affect renal function and should be distinguished from worsening nephropathy. Referral to an urologist is warranted to assess the potential need for intermittent self-catheterization. Nephropathy and Hypertension In up to 40% of type 1 diabetic patients, diabetic nephropathy may ultimately result in end-stage renal disease (ESRD). ESRD necessitates renal function replacement by hemodialysis, peritoneal dialysis, or renal transplantation if possible. Fortunately, chances of renal function preservation have dramatically improved over the last few decades because of better glycemic control and appropriate blood pressure management. Early stages of nephropathy tend to become clinically detectable about 10–12 years after diagnosis (Table 5). Annual screening for urinary albumin excretion and monitoring of serum creatinine level are recommended for all patients with a diabetes duration of 5 years or longer. Once nephropathy has progressed to persistent macroalbuminuria, prognosis worsens: about half

> 2.5 (men) > 3.5 (women) > 30 (men or women)

> 30 (men or women)

≥300 mg/24 h (macroalbuminuria)

Decreased Mild renal impairment 60–89 Moderate 30–59 Severe 15–29 90)

Normal or increased

20 degrees at the proximal interphalangeal joint are suggested as indications for surgery; high recurrence rates

Probably irreversible, relation to glycemic control controversial but optimizing control is advocated Splinting, local corticosteroid1 injection Ergonomic adjustments (e.g., computer workstations) Surgical decompression

Treatment options

18 ter Braak and Stades

Shoulder

Calcific periarthritis Limited Joint Mobility (LJM)

Often asymptomatic

Thickening and waxiness of the dorsal skin of the fingers Associated with LJM but also seen separately “Frozen shoulder” Reversible contraction of the glenohumeral joint capsule

Diabetic sclerodactyly

Adhesive capsulitis

Clinical, “locking phenomenon”

“Trigger finger”

Flexor tenosynovitis

Calcium deposits on shoulder X-ray

Clinical

Clinical

Diagnosis

Clinical Syndrome

Table 6 (Continued)

Corticosteroid injections Physiotherapy Often self-limited condition in 6–18 months

Immobilization in acute stage Local corticosteroid injection Surgery (outcome may be less successful in diabetes) No treatment known

Treatment options

Type 1 Diabetes 19

Diffuse idiopathic skeletal hyperostosis (DISH)

Also called: ankylosing hyperostosis or Forestier’s disease Metaplastic calcification and osteophyte formation of spinal ligaments and entheses (where tendons and ligaments attach to bone), mainly thoracic spine Association with diabetes uncertain

1 Note: Even locally injected corticosteroids may lead to considerable blood glucose disturbances

Skeleton

Clinical Autonomic testing, imagining studies May be associated with adhesive capsulitis Distinctive radiographic findings: flowing linear calcification and ossification of paravertebral ligaments

Reflex sympathetic dystrophy

“Shoulder hand syndrome” Association with diabetes uncertain

Diagnosis

Clinical Syndrome

Table 6 (Continued)

Physical therapy Analgesics

Regional sympathetic nerve block (may also be used diagnostically)

Treatment options

20 ter Braak and Stades

Type 1 Diabetes

21

For practical purposes, a “limb-oriented” overview of these conditions is given in Table 6. It should be stressed, however, that this may be an oversimplification. A classical example is Dupuytren’s disease, which may be observed in up to 42% of adults with diabetes mellitus, typically in patients with long-standing T1D. Dupuytren’s is characterized by thickening of the palmar fascia due to fibrosis with nodule formation and contracture, leading to flexion contractures of the digits, most commonly affecting the fourth and fifth digits. These abnormalities are quite readily observed during routine office visits and patients tend to bring up their complaints in an early stage because of perceived limitations in daily life. However, in fact there may be other related fibrosing diseases present as well that are more easily overlooked while patients may not bring forward complaints spontaneously. Other fibrosing conditions that are often seen concurrently with the palmar fibrosis of Dupuytren’s are nodular plantar fibrosis of the feet, nodular fasciitis of the popliteal fascia, and Peyronie’s disease of the penis (39). Limited joint mobility or diabetic cheiroarthropathy is attributed to abnormal collagen in connective tissue around joints and is readily recognized by the “prayer sign”: when asked to place opposite palmar sides of the hands and fingers together there is an inability to completely close the gap due to contractures in the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints (40, 41). At the “table top test” the patient is unable to flatten the palm of the hand when pressing it against the surface of a table. It is obvious that one or more of the above-mentioned conditions of the hand, especially when concurring in the presence of distal symmetric sensorimotor polyneuropathy (or one of the other clinical syndromes of neuropathy with involvement of the hands), lead to incapacities with respect to many aspects of daily life, including self-monitoring of blood glucose levels and injecting insulin. Foot Care Foot problems in diabetes are common and comprise ulceration, infection, and gangrene, thus resulting in serious morbidity and disability that may ultimately lead to amputation and even death. The lifetime risk of a foot ulcer for diabetic patients is about 15% (42). Amputation is predictive of a severely diminished life expectation, which in part reflects serious comorbidity and high age. In addition this may be indicative of the accessibility to appropriate care and the standard of delivered care (43). Screening, education, and early recognition are the mainstay of the prevention of more serious problems. All patients with diabetes should have an annual foot exam to assess risk factors for ulceration and amputation. At the same time, appropriate education with regard to foot self-care and risk factors can be delivered (Table 7) (44).

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ter Braak and Stades Table 7 Annual preventive foot care visit in primary care

Assessment of neuropathy, including a quantitative somatosensory threshold test Visual inspection of the foot and footwear

Screening for peripheral arterial disease Address educational issues

Assessment of self-care ability and involving a family member if indicated

Semmes–Weinstein 5.07 (10 g) monofilament at specific sites Skin lesions, especially between the toes and under the metatarsal heads Nail care Erythema, warmth, callus formation Bony deformities, joint mobility, gait and balance Shoes and socks History for claudication Assessment of pedal pulses Ankle brachial index Selection of appropriate footware Avoiding walking on bare feet Daily self-inspection of feet in case of diminished protective sensibility Importance to seek medical help in case of skin lesions and/or infection Visual impairment Diminished movement ability Impaired cognitive function

Once ulcers or infections are present, health care providers for diabetic patients should have a broad view on therapeutic possibilities. Since foot ulcers are generally multicausal in origin they call for a multidisciplinary approach, preferably using a protocol. In addition, effective record keeping and communication between team members are essential (45). Several classification systems for diabetic foot ulcers exist, but there is no consensus yet with respect to classifying or even describing foot ulcers. For clinical purposes, description of an ulcer should be thorough and clear including a photograph, if possible. Descriptions of wounds should include depth, extent, area, location, appearance, temperature, and odor. Wound depth is an important determinant of outcome (46, 47). Deep ulcers with cellulitis or abscess formation often involve osteomyelitis. From this stage on parenteral administration of antibiotics and hospitalization are indicated. Radiologic changes occur late in the course of osteomyelitis and negative radiographs certainly do not exclude it. In addition to osteomyelitis, assessment of arterial vascular disease is called for. Revascularization may be indicated in order to promote wound healing. Aggressive revascularization has been shown to decrease amputation at all levels (48, 49).

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TREATMENT Insulin Insulin therapy is mandatory for survival in T1D. The ideal insulin regimen mimics the physiological pattern of insulin secretion with low fasting insulin levels, a slow rise in insulin concentration in the early morning, and with postprandial peaks that closely follow the ingestion of carbohydrates and other food. The blood glucose profile over the day is preferably targeted to near normal glycemia with avoidance of hypoglycemia (see Table 8). The percentage of glucose binding to hemoglobin (HbA1c) reflects glucose concentrations in the preceding 4–8 weeks (50). The therapeutic goal is an HbA1c concentration around 7.0% to prevent microvascular and possibly macrovascular complications, unless hypoglycemia interferes (51, 52). The best approach to reach good glycemic control is either a multiple daily injection (MDI) regimen (also called basal bolus regimen) or continuous subcutaneous insulin infusion (CSII) using a pump. In MDI and CSII a preprandial bolus of rapid- or short-acting insulin is injected to prevent postprandial hyperglycemia. For basal insulin supply, intermediate- or long-acting insulin is administered or with CSII low doses of rapid-acting insulin are continuously infused (53). The dose of long- or intermediate-acting insulin is adjusted according to the fasting glucose concentration, but is limited by nocturnal hypoglycemia. In contrast, some patients show high fasting glucose concentration, which may be attributed to the so-called dawn phenomenon: the physiological early morning cortisol peak results in increased insulin resistance. Another pitfall

Table 8 Typical algorithm for insulin dosage adjustment aiming at near normal glycemia Blood Glucose (BG, mmol/L) target level

Preprandial dose of rapid/short acting insulin

Fasting BG

4–6

Preprandial BG

4–6

Postprandial BG (2 hours after) BG at bedtime

5–7 7–9

Bedtime dose of intermediate/long acting insulin Increase if BG > 6 (unless nocturnal hypoglycemia)

Increase dose before previous meal if BG > 6 Increase if BG > 7 Small extra bolus if BG > 9, review evening snacks

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is a rebound high fasting glucose after undetected nocturnal hypoglycemia, especially in MDI. One of the advantages of CSII is the possibility of a programmed increase of early morning insulin infusion and variable basal insulin infusion in accordance with exercise. Most currently available human insulin and insulin analogs are manufactured through recombinant DNA technology. Before DNA technology emerged, chemically modified pork insulin was used (derived from its pancreas) and is still available in some countries (54). Insulin analogs have a change in amino acid sequence of the β chain that influences the absorption rate (55). Insulin compounds are categorized by the rate of acting. Rapid-acting insulin analogs (lispro [Humalog], aspart [NovoRapid], and glulisine [Apidra]) are available as three different formulations, all showing comparable absorption rates. The peak insulin concentration is 40 min after injection and comes close to the postprandial insulin profile in healthy volunteers. The rapid-acting analogs show a rapid waning of action in 3–4 h. The advantage for patients is more flexibility since the time of injection is just before the meal and the frequency of hypoglycemia may be reduced with preservation of comparable HbA1c levels. The manufacturer of inhaled insulin Exubera, an effective alternative for rapid-acting subcutaneous insulin, recently stopped its production for financial economic reasons. Exubera was expensive and might have caused long-term adverse events with respect to alveolar function by inhaling insulin which is a potent growth factor. Regular short-acting insulin is unchanged human insulin. Due to its tendency to form hexamers in the subcutis, preparations of normal human insulin have a slower absorption rate after injection than the rapid-acting insulin analogs. The maximum insulin peak concentration is lower, occurs after 90 min, and the waning of action is 4–6 h. Due to a lag time for the onset of action, patients have to inject regular insulin 30 min before the meal, and because of its longer duration of action, patients often have to take a snack between meals to avoid hypoglycemia before the next meal. Intermediate-acting insulin is used as basal insulin since it results in a prolonged, relatively low insulin concentration. Neutral protamine Hagedorn (NPH) is human insulin in a buffered solution and has to be stirred before injection. Unfortunately, its absorption rate is quite variable. With an insulin peak level 6 h after an injection with NPH insulin, there is an increased risk of nocturnal hypoglycemia. Insulin detemir is an analog with a fatty acid chain that binds to albumin. Its time of action is 17.5 h and patients often end up with a twice daily regimen. Patients who use insulin detemir have less nocturnal hypoglycemia, lower fasting glucose, and less weight gain in a once daily regimen,

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compared to NPH. Disappointingly, recent data with a twice daily regimen of insulin detemir in type 2 diabetes did not show a difference in weight gain compared to other basal insulin regimens (56). Long-acting insulin glargine is an analog that is less soluble in the subcutaneously pH neutral environment because of a changed isoelectric point. The time of action is about 24 h and it results in lower fasting glucose concentration and less frequent nocturnal hypoglycemia. Results of a study reporting a head-to-head comparison of detemir and glargine in T1D are expected to be published soon. Both long-acting insulin analogs detemir and glargine may cause dermal irritation locally around the injection site. Mixtures of rapid- or short-acting insulin in combination with NPH are available and these are given twice daily. Its use is no longer indicated in the majority of type 1 patients. However, a mixture can be a solution in T1D patients with a short life expectancy or difficulties with the management of an MDI regimen, e.g., in the presence of cognitive impairment. Metformin is potentially of use in overweight T1D patients with decreased insulin sensitivity calling for high insulin dosages. Metformin inhibits gluconeogenesis and possibly improves insulin sensitivity. A mean decrease of HbA1c levels of about 1% or a decrement of insulin dosages and weight loss has been reported in studies with metformin added to insulin therapy in T1D (57, 58). Most patients with CSII use a rapid-acting insulin analog, since postprandial glucose is better controlled. A recent meta-analysis reported that CSII improved metabolic control (HbA1c), in combination with a decreased frequency of severe hypoglycemia, especially in patients suffering from frequent severe hypoglycemia (53). However, patients eligible for CSII should be motivated by proper education from their health care providers, to perform frequent self-monitoring of blood glucose (SMBG) in order to engage in taking responsibility for self-management. In patients on CSII there is an increased risk of ketoacidosis due to the absence of a subcutaneous insulin reservoir, especially in case of potential technical problems with the pump or its supplies. Currently pumps are becoming available that are able to continuously measure subcutaneous glucose levels and that notify patients by an alarm in case of high or low glucose values. However, closed-loop systems are not available yet. Devices Patients receive instructions for SMBG using a small portable meter. Insulin administration is then adjusted using algorithms based on fasting, preprandial, postprandial, and evening glucose concentrations to reach target blood glucose values (see Table 3). Blood glucose measurement devices are

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reasonably accurate and precise in the euglycemic range, but less exact in the hypoglycemic range. In patients with frequent hypoglycemia or extremely variable blood glucose values use of a continuous glucose monitoring system (CGMS) in combination with a diary may uncover underlying problems and give patients insight into their behavioral actions and reactions as well as the way their body responds. Insulin injection systems are available in a variety of disposable or reusable devices. For patients with impaired vision, magnifying or sensibleaudible options are available, which enable patients to keep track of their adjusted insulin doses and ultimately may help them to preserve their independence in daily life. Patient’s preferences should be the predominant determinants for the injection system used and the type of insulin within its class that is prescribed.

In-Hospital Blood Glucose Monitoring Intercurrent morbidity, such as infections or trauma, frequently worsens hyperglycemia by means of a temporarily diminished sensitivity for insulin, while on the other hand hypoglycemia is at stake in the presence of abdominal discomfort and diminished food intake. Consequently, in order to prevent ketoacidosis due to the absolute deficiency of insulin, patients should obtain either a low dose of basal insulin (50% of their usual dosage) or continuous intravenous insulin infusion. In critical care, currently, blood glucose target levels < 6.1 mmol/l are widely implemented because of accumulating evidence for improved survival. Some studies show conflicting data of the hazards of hypoglycemia and related mortality (see also Hypoglycemia in People with Diabetes, Chapter 6) (51). Glycemic targets in medical–surgical wards are not definite, but data suggest improved outcome at lower levels (see also Treatment of Hyperglycemia, Chapter 9). In general, glucose levels below 10 mmol/l are advised in hospitalized patients with avoidance of hypoglycemia.

LIFESTYLE Patients are encouraged to maintain an active lifestyle and to exercise. They should receive advice on how to modify insulin dosage according to the amount and duration of exercise to avoid related hypoglycemia and potential late hypoglycemia at night. Vigorous exercise can deteriorate severe hypertension, retinopathy, and autonomic neuropathy and should be avoided without previous medical consultation (51).

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Diet Patients with normal body weight do not have dietary restrictions with respect to carbohydrate intake, but even so they should monitor their carbohydrate intake and adjust the dose of short-acting insulin based on experience or a personalized calculation of carbohydrate/insulin ratio. Both lean and obese patients should be advised to restrict saturated fats and trans-fats. The use of alcohol is not prohibited, but should be moderate. Binge drinking of alcoholic beverages can induce late hypoglycemia (51). Smoking should be discouraged at all times, and patients should be offered both mental and pharmacological support to quit. Management of Risk Factors for Cardiovascular Disease According to current standards, blood pressure is monitored routinely at every visit (51). Measurement of fasting lipids should be obtained annually. If the recommended LDL target value < 2.6 mmol/l is not met after 6 months with lifestyle modifications consisting of diet and exercise, pharmacological therapy with statins is indicated. If statins are not tolerated, a 40% reduction from baseline is alternatively considered a reasonable goal (51). Combination therapy to reach treatment targets may be prescribed but their effect is not (yet) confirmed in trials with hard endpoints. Aspirin therapy is indicated in patients with cardiovascular disease and may also be considered in case of increased cardiovascular risk, such as in diabetic nephropathy (51). β-Cell Transplantation For years, combined renal and pancreatic transplantation has been performed in type 1 diabetic patients with end-stage renal failure or dialysis. Those patients received a renal graft and a pancreas anastomosis on the bladder for secretion of exocrine pancreas hormones and digestive fluids (59). After transplantation, patients initially become independent of insulin. Transplantation of pancreas tissue only, without renal transplantation, is not being performed because of an alleged disadvantageous balance between profits of insulin independence and disproportional low graft survival with recurrent insulin dependence and because of adverse effects of immunosuppression such as hypertension, dyslipidemia, neurotoxicity and nephrotoxicity, peripheral edema, and mouth ulcers. During the last decade, β-cell or islet transplantation is gaining terrain by improvement of the technical procedures involved in the isolation of islets without exocrine pancreatic tissue by the injection and infusion of islets in the portal vein area. With islet transplantation, the graft survival for complete independence of insulin has improved from 20% graft survival after 1 year to 20% insulin

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independence after 3 years (59, 60). However, if insulin substitution is needed again after β-cell transplantation, good metabolic control is much easier to reach with far less hypoglycemia and with restoration of hypoglycemia awareness. This strategy is severely limited by the requirement of about five donors in order to harvest enough islets for one recipient. Recent research also shows possibilities to preserve β-cell function: Short-term treatment with CD3 antibody was shown to preserve residual β-cell function for at least 18 months in patients with recent-onset T1D (61).

LIVING WITH DIABETES Being diagnosed with T1D has lifetime consequences for daily life for the patient himself (who is at that time often still a child) and for his or her family, friends, and other acquaintances, e.g., at school, work, and during sports. Such widely accepted social activities as having a meal in a restaurant, having a drink or two in a café, and even hurrying to catch a train have a different impact on people with diabetes than on those who are not dependent on exogenous insulin. In addition, diabetes also influences the perspective on diverse matters as career choices, starting a family, and getting a mortgage. Having diabetes raises issues concerning one’s driver’s license, job applications, and absence from work or school due to visiting the doctor and other health care workers or related to intercurrent sequelae such as (nightly) hypoglycemic spells. Insurances (medical, disability, life insurance) generally have strict policies resulting in more difficult and sometimes denied admittance and charge higher rates even for applicants with well-controlled diabetes without complications. The above may clearly result in stress, grief, frustration, and disappointment, as may be the case in many other chronic conditions. In T1D this is further complicated by the fact that managing the disease on a day-to-day basis is based on self-care consisting of regular insulin injections and an extensive set of do’s and do not’s regarding lifestyle. Psychological distress in its turn may have negative effects on one’s ability to adhere to self-care and may thus further worsen quality of life, in terms of mental health with respect to short- and long-term complications. More specifically, anxiety related to hypoglycemia may result in a vicious circle ensuing in self-treatment strategies with avoidance of low blood glucose levels and poor glycemic control. Appropriate education and support with respect for the autonomy of persons with diabetes is therefore extremely important. Paternalism and moralism should be avoided, and health care workers caring for patients with diabetes and their families need to be trained in counseling techniques. Psychological interventions including psychoanalytically informed therapies, cognitive behavior therapy, and family systems therapy are widely used

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attempting to improve both psychological well-being and glycemic control. A meta-analysis of the results of psychological interventions showed a small but significant absolute reduction in glycated hemoglobin levels in children (including adolescents) of nearly 0.5% and an improvement with respect to psychological distress (62). Unfortunately, neither of these was the case in adults. Education of people with diabetes is a comprehensive task and involves teamwork by a team that comprises at least a nurse educator, a dietician, and a physician. It is, however, essential that individuals with diabetes assume an active role in their care themselves, since appropriate self-care behavior is the cornerstone of the treatment of diabetes.

REFERENCES 1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008; 31(Suppl 1):S55–S60. 2. Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 2000; 23(10):1516–1526. 3. Neu A, Willasch A, Ehehalt S, Hub R, Ranke MB. Ketoacidosis at onset of type 1 diabetes mellitus in children–frequency and clinical presentation. Pediatr Diabetes 2003; 4(2): 77–81. 4. Ostman J, Lonnberg G, Arnqvist HJ, et al. Gender differences and temporal variation in the incidence of type 1 diabetes: results of 8012 cases in the nationwide Diabetes Incidence Study in Sweden 1983–2002. J Intern Med 2008; 263(4):386–394. 5. Bruno G, Merletti F, Biggeri, A, et al. Increasing trend of type I diabetes in children and young adults in the province of Turin (Italy). Analysis of age, period and birth cohort effects from 1984 to 1996. Diabetologia 2001; 44(1):22–25. 6. Eisenbarth GS. Update in type 1 diabetes. J Clin Endocrinol Metab 2007; 92(7):2403–2407. 7. Stenstrom G, Gottsater A, Bakhtadze E, Berger B, Sundkvist G. Latent autoimmune diabetes in adults: definition, prevalence, beta-cell function, and treatment. Diabetes 2005; 54(Suppl 2):S68–S72. 8. Cardwell CR, Carson DJ, Patterson CC. No association between routinely recorded infections in early life and subsequent risk of childhood-onset Type 1 diabetes: a matched case-control study using the UK General Practice Research Database. Diabet Med 2008; 25(3):261–267. 9. Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: immunogenetics and longterm follow-up. J Clin Endocrinol Metab 2003; 88(7):2983–2992. 10. Kruszynska YT. Normal metabolism: the physiology of fuel homeostasis. In: Pickup JC, Williams G, eds. Textbook of Diabetes. Oxford: Blackwell Science Ltd, 2006. 11. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414(6865):799–806. 12. Shepherd PR, Kahn BB. Glucose transporters and insulin action–implications for insulin resistance and diabetes mellitus. N Engl J Med 1999; 341(4):248–257. 13. Gibson TB, Lawrence MC, Gibson CJ, et al. Inhibition of glucose-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 by epinephrine in pancreatic beta-cells. Diabetes 2006; 55(4):1066–1073. 14. Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes 2005; 54(12):3592–3601. 15. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368(9548):1696–1705.

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16. Hyperglycemic crises in diabetes. Diabetes Care 2004; 27(Suppl 1):S94. 17. ter Braak EW, Appelman AM, van de LM, Stolk RP, van Haeften TW, Erkelens DW. Clinical characteristics of type 1 diabetic patients with and without severe hypoglycemia. Diabetes Care 2000; 23(10):1467–1471. 18. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 2005; 28(5):1245–1249. 19. Robinson RT, Harris ND, Ireland RH, Lee S, Newman C, Heller SR. Mechanisms of abnormal cardiac repolarization during insulin-induced hypoglycemia. Diabetes 2003; 52(6): 1469–1474. 20. Murphy NP, Ford-Adams ME, Ong KK, et al. Prolonged cardiac repolarisation during spontaneous nocturnal hypoglycaemia in children and adolescents with type 1 diabetes. Diabetologia 2004; 47(11):1940–1947. 21. The Diabetes Control and Complications Trial Research Group. The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. N Engl J Med 1993; 329(14):977–986. 22. Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes. N Engl J Med 2005; 353(25):2643–2653. 23. Brownlee M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes 2005; 54(6):1615–1625. 24. Lecaire T, Palta M, Zhang H, Allen C, Klein R, D’Alessio D. Lower-than-expected prevalence and severity of retinopathy in an incident cohort followed during the first 4–14 years of type 1 diabetes: the Wisconsin Diabetes Registry Study. Am J Epidemiol 2006; 164(2): 143–150. 25. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med 1993; 329(14):977–986. 26. Wilkinson CP, Ferris FL, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003; 110(9):1677–1682. 27. American Diabetes Association. Standards of Medical Care in Diabetes –2008. Diabetes Care 2008; 31(Suppl 1):S12–S54. 28. Boulton AJM, Vinik AI, Arezzo JC, et al. Diabetic Neuropathies: A statement by the American Diabetes Association. Diabetes Care 2005; 28(4):956–962. 29. Molitch ME, DeFronzo RA, Franz MJ, et al. Nephropathy in diabetes. Diabetes Care 2004; 27(Suppl 1):S79–S83. 30. Freedman BI, Bostrom M, Daeihagh P, Bowden DW. Genetic Factors in Diabetic Nephropathy. Clin J Am Soc Nephrol 2007; 2(6):1306–1316. 31. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med 1993; 329(14):977–986. 32. Freedman BI, Bostrom M, Daeihagh P, Bowden DW. Genetic Factors in Diabetic Nephropathy. Clin J Am Soc Nephrol 2007; 2(6):1306–1316. 33. American Diabetes Association. Standards of Medical Care in Diabetes – 2008. Diabetes Care 2008; 31(Suppl 1):S12–S54. 34. Krolewski AS, Kosinski EJ, Warram JH, et al. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol 1987; 59(8): 750–755. 35. Krolewski AS, Kosinski EJ, Warram JH, et al. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol 1987; 59(8): 750–755. 36. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med 1993; 329(14):977–986. 37. American Diabetes Association. Standards of Medical Care in Diabetes – 2008. Diabetes Care 2008; 31(Suppl 1):S12–S54.

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38. Hordon LD. Musculoskeletal complications in diabetes mellitus. UpToDate version 16.2. 15-9-2006. http://www.uptodate.com/online/content/topic.do?topicKey=muscle/10289& selectedTitle=2∼150&source=search_result. Accessed April 6, 2009. 39. Wooldridge WE. Four related fibrosing diseases. When you find one, look for another. Postgrad Med 1988; 84(2):269–271, 274. 40. Kim RP, Edelman SV, Kim DD. Musculoskeletal complications of diabetes mellitus. Clinical Diabetes 2001; 19: 132–135. 41. Browne DL, McCrae FC, Shaw KM. Musculoskeletal disease in diabetes. Pract Diab Int 2001; 18:62–64. 42. Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet 2003; 361(9368):1545–1551. 43. American Diabetes Association. Standards of Medical Care in Diabetes – 2008. Diabetes Care 2008; 31(Suppl 1):S12–S54. 44. American Diabetes Association. Standards of Medical Care in Diabetes – 2008. Diabetes Care 2008; 31(Suppl 1):S12–S54. 45. van Houtum WH. Barriers to the delivery of diabetic foot care. The Lancet 2005; 366(9498):1678–1679. 46. American Diabetes Association. Standards of Medical Care in Diabetes – 2008. Diabetes Care 2008; 31(Suppl 1):S12–S54. 47. Consensus Development Conference on Diabetic Foot Wound Care: 7-8 April 1999, Boston, Massachusetts. American Diabetes Association. Diabetes Care 1999; 22(8): 1354–1360. 48. American Diabetes Association. Standards of Medical Care in Diabetes – 2008. Diabetes Care 2008; 31(Suppl 1):S12–S54. 49. Consensus Development Conference on Diabetic Foot Wound Care: 7-8 April 1999, Boston, Massachusetts. American Diabetes Association. Diabetes Care 1999; 22(8): 1354–1360. 50. Test of glycemia in diabetes. American Diabetes Association. Diabetes Care 2004; 27(Suppl 1):S91–S93. 51. American Diabetes Association. Standards of medical care in diabetes – 2008. Diabetes Care 2008; 31(Suppl):S12–S54. 52. Robinson RT, Harris ND, Ireland RH, Macdonald IA, Heller SR. Changes in cardiac repolarization during clinical episodes of nocturnal hypoglycaemia in adults with Type 1 diabetes. Diabetologia 2004; 47(2):312–315. 53. Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: metaanalysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion. Diabet Med 2008; 25(7):765–774. 54. Insulin administration. American Diabetes Association. Diabetes Care 2004; 27(Suppl 1):S106–S109. 55. Hirsch IB. Insulin analogues. N Engl J Med 2005; 352(2):174–183. 56. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008; 51(3):408–416. 57. Khan AS, McLoughney CR, Ahmed AB. The effect of metformin on blood glucose control in overweight patients with Type 1 diabetes. Diabet Med 2006; 23(10):1079–1084. 58. Lund SS, Tarnow L, Astrup Asb, et al. Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. PLoS ONE 2008; 3(10):e3363. 59. Bertuzzi F, Ricordi C. Beta-cell replacement in immunosuppressed recipients: old and new clinical indications. Acta Diabetol 2007; 44(4):171–176. 60. Merani S, Shapiro AM. Current status of pancreatic islet transplantation. Clin Sci (Lond) 2006; 110(6):611–625. 61. Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005; 352(25):2598–2608.

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62. Winkley K, Ismail K, Landau S, Eisler I. Psychological interventions to improve glycaemic control in patients with type 1 diabetes: systematic review and meta-analysis of randomised controlled trials. BMJ 2006; 333(7558):65. 63. Service FJ, Rizza RA, Zimmerman BR, Dyck PJ, O’Brien PC, Melton LJ 2rd. The classification of diabetes by clinical and C-peptide criteria. A prospective population-based study. Diabetes Care 1997; 20(2):198–201.

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Type 2 Diabetes Hermes J. Florez, Alex A. Sanchez, and Jennifer B. Marks CONTENTS I NTRODUCTION D IAGNOSIS E PIDEMIOLOGY PATHOGENESIS P REVENTION OR D ELAY OF T YPE 2 D IABETES M ANAGEMENT N EED FOR I MPROVING D IABETES C ARE R EFERENCES

Abstract Type 2 diabetes (T2D) is the most common form of diabetes, a metabolic disorder characterized by hyperglycemia resulting from defects in insulin action, insulin secretion, or both. Early diagnosis of T2D and the high-risk category of pre-diabetes may help reduce the associated public health and clinical burden. Available diagnostic strategies include fasting plasma glucose, oral glucose tolerance test, and casual plasma glucose in the presence of symptoms of hyperglycemia. Potential use of hemoglobin A1c as part of the strategy for screening and diagnosis has been recently proposed. Those with risk factors for T2D should be targeted including patients with overweight/obesity, those with family history of T2D, those aged 45 years and older, race/ethnic minorities (such as Native Americans, African Americans, Latinos, and Asian Americans), women with history of gestational diabetes, and those with metabolic syndrome abnormalities (high blood pressure, low HDL cholesterol, and high triglycerides). Lifestyle modification (i.e., weight loss through diet and increased physical activity) has proven effective in reducing incident T2D in high-risk groups. Prevention trials using pharmacological therapy (metformin, α-glucosidase From: Contemporary Diabetes: Diabetes and the Brain Edited by: G. J. Biessels, J. A. Luchsinger (eds.), DOI 10.1007/978-1-60327-850-8_2  C Humana Press, a part of Springer Science+Business Media, LLC 2009 33

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inhibitors, or thiazolidinediones) have also reported a significant lowering of the incidence of T2D. As a chronic condition, T2D requires continuous care to prevent damage to various organs, including the eyes, kidney, nervous system, and cardiovascular system. Appropriate glycemic control, blood pressure and lipid management, nutrition and physical activity, taking into account functional status and comorbidities, are needed to prevent microvascular and macrovascular complications. A variety of oral antihyperglycemic agents, which target different mechanisms in the pathogenesis of T2D, are as follows: insulin sensitizers, insulin secretagogues, α-glucosidase inhibitors, and the new dipeptidyl peptidase (DPP)-IV inhibitors. Injectable agents for the treatment of insulindeficient T2D include traditional insulin preparations, newer insulin analogs, amylin, and incretin mimetics. Additional aspects of T2D management in the older adult include the assessment of geriatric syndromes and psychosocial screening. Efforts to improve T2D care following recommended guidelines are still very much needed. Key words: Type 2 Diabetes; Diagnosis; Epidemiology; Management; Insulin resistance; Insulin secretion.

Prevention;

INTRODUCTION Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia, which can result from defects in insulin secretion, insulin action, or both. Diabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce long-term complications.

DIAGNOSIS The American Diabetes Association (ADA) diagnostic criteria for diabetes and the two high-risk categories of pre-diabetes, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), updated in 2003 are defined in Table 1 (1). There are three ways to diagnose diabetes. Because of simplicity of use, acceptability to patients, and low cost, the fasting plasma glucose (PG) is the preferred diagnostic test. In the presence of symptoms of diabetes (polyuria, polydipsia, weight loss, etc.), a casual plasma glucose of greater or equal than 200 mg/dl is diagnostic. The 75-g oral glucose tolerance test (OGTT) is more sensitive and modestly more specific than fasting PG, but it is less reproducible and less frequently performed in clinical settings. In the absence of unequivocal hyperglycemia, any test used to diagnose diabetes must be confirmed on a subsequent day by a PG measured either in the fasting state or 2 h after an oral glucose load.

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Table 1 The diagnostic criteria for diabetes and the classification of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT)

Normal IFG IGT Diabetes

FPG (mg/dl)

2-HPG (mg/dl)

Sx of diabetes + CPG